The goal of the proposed research is to characterize novel isoenzyme-selective inhibitors of histone deacetylase 6 (HDAC6) to enable human clinical investigation. Following proteasome inhibition, perinuclear aggregates of insoluble ubiquitinated proteins (termed 'aggresomes') accumulate and are degraded by autophagy. HDAC6 is a cytosolic protein mediating interactions between ubiquitinated proteins, alphatubulin and the dynein motor complex. Genetic studies of aggresome formation have demonstrated a requirement for HDAC6 enzyme function. Recent work by the candidate has credentialed HDAC6 as a cancer target in multiple myeloma, a model system for mechanistic studies of protein catabolism. Though many HDAC inhibitors are presently being prosecuted in early phase clinical development, drugs targeting HDAC6 have not been realized. Using the HDAC6-selective tool compound, tubacin, and the proteasome inhibitor, bortezomib, the applicant devised a novel anticancer strategy targeting protein catabolism with activity in preclinical models of multiple myeloma, pancreatic and ovarian cancer. Pharmacologic liabilities limit the therapeutic development of tubacin. Recent research by the applicant has resulted in a new class of highly potent bifunctional HDAC6 inhibitors (BH6-54A and BH6-1584). This research proposal outlines a biochemical study of bivalent molecular recognition and a late-phase preclinical drug development plan: in vitro toxicology, pharmacologic studies in rodents and efficacy testing in murine models of multiple myeloma. The candidate is a physician-scientist with clinical training in medical oncology and hematology. He has completed two years of post-doctoral research in chemical biology focusing on ligand discovery, protein degradation and HDAC6. His long-term goal is to establish and direct an academic research laboratory applying novel strategies in chemical biology to clinically-relevant challenges in malignant hematology. The proposed research will be carried out under the sponsorship of two mentors: Dr. Kenneth Anderson in the Division of Hematologic Neoplasia of the Dana-Farber Cancer Institute and Dr. Stuart Schreiber in the Chemical Biology Program of the Broad Institute of Harvard and MIT. This award will support a unique training experience in translational research and chemical biology, and will establish an academic pathway for the discovery and development of experimental cancer therapeutics.